The role of reverse cholesterol transport in animals and humans and relationship to atherosclerosis

Abstract

Reverse cholesterol transport (RCT) is a term used to describe the efflux of excess cellular cholesterol from peripheral tissues and its return to the liver for excretion in the bile and ultimately the feces. It is believed to be a critical mechanism by which HDL exert a protective effect on the development of atherosclerosis. In this paradigm, cholesterol is effluxed from arterial macrophages to extracellular HDLbased acceptors through the action of transporters such as ABCA1 and ABCG1. After efflux to HDL, cholesterol may be esterified in the plasma by the enzyme lecithin:cholesterol acyltransferase and is ultimately transported from HDL to the liver, either directly via the scavenger receptor BI or after transfer to apolipoprotein B-containing lipoproteins by the cholesteryl ester transfer protein. Methods for assessing the integrated rate of macrophage RCT in animals have provided insights into the molecular regulation of the process and suggest that the dynamic rate of macrophage RCT is more strongly associated with atherosclerosis than the steady-state plasma concentration of HDL cholesterol. Promotion of macrophage RCT is a potential therapeutic approach to preventing or regressing atherosclerotic vascular disease, but robust measures of RCT in humans will be needed in order to confidently advance RCT-promoting therapies in clinical development.-

Empagliflozin, via Switching Metabolism Toward Lipid Utilization, Moderately Increases LDL Cholesterol Levels Through Reduced LDL Catabolism

“…In addition, our in vivo experiments also highlighted potential antiatherogenic mechanisms induced by empagliflozin, such as LDLand macrophage-derived fecal cholesterol excretion. Macrophage-to-feces reverse cholesterol transport is known to be inversely correlated with atherosclerosis (18), and an enhanced excretion of LDL-derived cholesterol in the feces theoretically prevents its accumulation in the arterial wall. Whether these mechanisms, besides body weight loss and blood pressure lowering, contribute to the reduced cardiovascular risk in patients treated with empagliflozin (17) remains to be further investigated.…”

Amyloidogenic Mutation Promotes Fibril Formation of the N-terminal Apolipoprotein A-I on Lipid Membranes

“…Apolipoprotein A-I (apoA-I) 2 is the major protein component of plasma high-density lipoprotein (HDL) and plays a central role in reverse cholesterol transport, a process by which excess cholesterol in peripheral cells is transferred to the liver for catabolism (1)(2)(3). In humans, the apoA-I molecule (243 residues) folds into two tertiary structure domains, comprising an N-terminal ␣-helix bundle spanning residues 1-187 and a separate less organized C-terminal region spanning the remainder of the molecule (4 -6).…”

Cholesteryl ester transfer protein: The controversial relation to atherosclerosis and emerging new biological roles

“…Recent in vivo experimental data by Rader's group support the concept that specific macrophage-linked RCT is mechanistically related to atherogenesis (19). Early cell-based studies had already raised evidence that CETP might contribute directly to decreased lipid accumulation in arterial foam cells.…”

“…In short, RCT represents an HDLdependent pathway by which cholesterol is removed from tissues and delivered to the liver for excretion from the body. After decades of research, RCT was shown to occur through a complex sequence of reactions involving many steps and players, including specific cellular transporters, receptors, and extracellular HDL acceptors and enzymes (19) (Fig. 2).…”